The present invention is related to novel compounds, to a process for their preparation, their use and pharmaceutical compositions comprising the novel compounds. Also intermediates to the compounds of the present application are claimed. The novel compounds are useful in therapy, and in particular for the treatment of pain.
The xcex4 receptor has been identified as having a role in many bodily functions such as circulatory and pain systems. Ligands for the xcex4 receptor may therefore find potential use as analgesics, and/or as antihypertensive agents. Ligands for the xcex4 receptor have also been shown to possess immunomodulatory activities.
The identification of at least three different populations of opioid receptors (xcexc, xcex4 and xcexa) is now well established and all three are apparent in both central and peripheral nervous systems of many species including man. Analgesia has been observed in various animal models when one or more of these receptors has been activated.
With few exceptions, currently available selective opioid xcex4 ligands are peptidic in nature and are unsuitable for administration by systemic routes. Some non-peptidic xcex4 antagonists have been available for some time (see Takemori and Portoghese, 1992, Ann. Rev. Pharmacol. Tox., 32: 239-269. for review). These compounds, e.g. naltrindole, suffer from rather poor (i.e.,  less than 10-fold) selectivity for the xcex4 receptor vs. xcexc receptor binding and exhibit no analgesic activity, a fact which underscores the need for the development of highly selective non-peptidic xcex4 ligands.
Thus, the problem underlying the present invention was to find new analgesics having improved analgesic effects, but also with an improved side-effect profile over current xcexc agonists and potential oral efficacy.
Analgesics that have been identified and are existing in the prior art have many disadvantages in that they suffer from poor pharmacokinetics and are not analgesic when administered by systemic routes. Also, it has been documented that preferred compounds, described within the prior art, show significant convulsive effects when administered systemically.
The problem mentioned above has now been solved by developing novel substituted phenyl compounds, as will be described below.
The novel compounds according to the present invention are defined by the general formula I 
wherein
R1 is selected from anyone of
(i) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, where each alkyl, alkenyl or alkynyl may optionally be substituted by one or more aromatic or heteroaromatic substituents;
(ii) C3-C7 cycloalkyl optionally substituted by anyone of C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
(iii) hydrogen, halogen or C1-C6 alkoxy;
(iv) C6-C10 aryl;
(v) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
Q is selected from any of CH3; 
xe2x80x83wherein
R2, R3 and R4 is each and independently selected from any of
(i) C6-C10 aryl; or
(ii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and
xe2x80x83wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined below;
(iii) hydrogen;
(iv) a straight or branched C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
(v) saturated or unsaturated C3-C10 cycloalkyl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined below;
Y is each and independently selected from any of hydrogen, CH3; xe2x80x94(CH2)p1CF3; halogen; C1-C3 alkoxy; hydroxy; xe2x80x94NO2; xe2x80x94OCF3; xe2x80x94CONRaRb; COORa; xe2x80x94CORa; xe2x80x94(CH2)p2NRaRb; xe2x80x94(CH2)p3CH3, (CH2)p4SORaRb; xe2x80x94(CH2)p5SO2Ra; xe2x80x94(CH2)p6SO2NRa; C4-C8(alkyl-cycloalkyl) wherein alkyl is C1-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl; 1 or 2 heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O; and oxides such as N-oxides or sulfoxides; and wherein
xe2x80x83Ra and Rb is each and independently selected from hydrogen, a branched or straight C1-C6 alkyl, C1-C6 alkenyl, C3-C8 cycloalkyl; and wherein
xe2x80x83p1, p2, p3, p4, p5 and p6 is each and independently 0, 1 or 2.
Within the scope of the invention are also pharmaceutically acceptable salts of the compounds of the formula I, as well as isomers, hydrates, isoforms and prodrugs thereof.
Preferred compounds according to the invention are compounds of the formula I wherein
Q is 
xe2x80x83wherein
R2 and R4 is each and independently selected from any of
(i) C6-C10 aryl; or
(ii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and
xe2x80x83wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(iii) a straight or branched C1-C6 alkyl or C2-C6 alkynyl;
(iv) saturated or unsaturated C3-C6 cycloalkyl, optionally and independently substituted by one or more heteroaryl(s) having from 5 to 10 atoms and the heteroatom(s) being selected from any of S, N and O and wherein the heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y wherein each Y is as defined above;
Particularly preferred compounds according to the invention are compounds of the formula I wherein
R1 is
(i) phenyl optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(ii) naphthyl optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
(iii) heteroaryl having from 5 to 10 atoms and the heteroatom being selected from any of S, N and O; and wherein the aryl and heteroaryl may optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above;
Q is 
wherein
R2 is
(i) phenyl optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above; or
(ii) naphthyl optionally and independently be substituted by 1 or 2 substituents Y where each Y is as defined above.
By xe2x80x9chalogenxe2x80x9d we mean chloro, fluoro, bromo and iodo.
By xe2x80x9carylxe2x80x9d we mean an aromatic ring having 6 or 10 carbon atoms, such as phenyl and naphthyl.
By xe2x80x9cheteroarylxe2x80x9d we mean an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
By xe2x80x9cisomersxe2x80x9d we mean compounds of the formula I, which differ by the position of their functional group and/or orientation. By xe2x80x9corientationxe2x80x9d we mean stereoisomers, diastereoisomers, regioisomers and enantiomers.
By xe2x80x9cisoformsxe2x80x9d we mean compounds of the formula I which differ in the relative physical arrangement of molecules by crystal lattice, such that isoforms refer to various crystalline compounds and amorphous compounds.
By xe2x80x9cprodrugxe2x80x9d we mean pharmacologically acceptable derivatives, e.g. esters and amides, such that the resulting biotransformation product of the derivative is an active form of the drug. The reference by Goodman and Gilmans, The Pharmacological basis of Therapeutics, 8th ed., McGraw-Hill, Int. Ed. 1992, xe2x80x9cBiotransformation of Drugs, p. 13-15, describing prodrugs generally, is hereby incorporated by reference.
The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.
Compounds of the invention are useful as immunomodulators, especially for autoimmune diseases, such as arthritis, for skin grafts, organ transplants and similar surgical needs, for collagen diseases, various allergies, for use as anti-tumour agents and anti viral agents.
Compounds of the invention are useful in disease states where degeneration-or dysfunction of opioid receptors is present or implicated in that paradigm. This may involve the use of isotopically labelled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).
Compounds of the invention are useful for the treatment of diarrhoea, depression, urinary incontinence, various mental illnesses, cough, lung oedema, various gastrointestinal disorders, spinal injury and drug addiction, including the treatment of alcohol, nicotine, opioid and other drug abuse and for disorders of the sympathetic nervous system for example hypertension.
Compounds of the invention are useful as an analgesic agent for use during general anaesthesia and monitored anaesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anaesthetic state (e.g. Amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anaesthetics, hypnotica, anxiolytics, neuromuscular blockers and opioids.
The compounds of the present invention in isotopically labelled form are useful as a diagnostic agent.
Also within the scope of the invention is the use of any of the compounds according to the formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment.
The best mode of performing the invention known at present, is to use the compounds according to Example 1 (compound 11), Example 8 (compound 18), Example 9 (compound 19), Example 10 (compound 20) and Example 11 (compound 21). The numbering of the compounds is in accordance with the numbering in the Schemes presented in the following.
The compounds of the present invention may be prepared by following the synthetic routes described in Scheme 1 below.

As shown in Scheme 1 above, compounds of the formula I may be obtained from commercially available bis-amino-xylylene (compound II). Compound II is converted into mono-(diBoc)-guanidinomethyl derivative m using a protected guanylating reagent such as 1-H-pyrazole-1-(N,N-bis(tert-butoxycarbonylcarboxamidine) in an organic solvent such as THF.
The secondary amine of the formula V may be generated using a reductive amination step where the compound of the formula III is reacted with an aldehyde (compound IV wherein R1 is as defined in formula I above), in the presence of an acid such as acetic acid or a Lewis acid such as ZnCl2 and in a protic solvent such as methanol or ethanol in the presence of a reducing agent such as sodium cyanoborohydride.
Compounds of the formula VI may be obtained by performing an acylating reaction where compound V is mixed with an acid chloride or other appropriate acylating reagent such as an acid anhydride in a solvent such as methylene chloride and in the presence of a tertiary amine as base, such as triethylamine.
Finally, compounds of the formula I may be obtained by cleavage of the Boc protecting group with an acid such as aqueous hydrochloric acid or by using organic acid such as trifluoroacetic acid in a solvent such as methylene chloride.
In the formulas of Scheme 1 above, R1 and Q are as defined in formula I above.